WO2002080914A2 - Utilisation de composes imidazo[1,2-a]-pyridine substitues comme medicaments - Google Patents

Utilisation de composes imidazo[1,2-a]-pyridine substitues comme medicaments Download PDF

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Publication number
WO2002080914A2
WO2002080914A2 PCT/EP2002/003795 EP0203795W WO02080914A2 WO 2002080914 A2 WO2002080914 A2 WO 2002080914A2 EP 0203795 W EP0203795 W EP 0203795W WO 02080914 A2 WO02080914 A2 WO 02080914A2
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radical
unsubstituted
monosubstituted
aryl
alkyl
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PCT/EP2002/003795
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German (de)
English (en)
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WO2002080914A3 (fr
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Corinna Maul
Hagen-Heinrich Hennies
Bernd Sundermann
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Grünenthal GmbH
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Priority to MXPA03008965A priority Critical patent/MXPA03008965A/es
Priority to CA002442996A priority patent/CA2442996A1/fr
Priority to HU0401302A priority patent/HUP0401302A2/hu
Priority to JP2002578953A priority patent/JP2004529141A/ja
Priority to EP02727529A priority patent/EP1372647A2/fr
Publication of WO2002080914A2 publication Critical patent/WO2002080914A2/fr
Publication of WO2002080914A3 publication Critical patent/WO2002080914A3/fr
Priority to US10/678,645 priority patent/US20040142961A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of substituted imidazo [1, 2-a] pyridine compounds and their physiologically tolerable salts as inhibitors for nitrogen monoxide synthase and for the production of medicaments.
  • NO synthase nitrogen monoxide synthase
  • the medicinal products are said to be suitable for the treatment of migraines, septic shock, neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease or Huntington's disease, inflammation, inflammation pain, cerebral ischemia, diabetes, meningitis, arteriosclerosis or for wound healing.
  • neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease or Huntington's disease, inflammation, inflammation pain, cerebral ischemia, diabetes, meningitis, arteriosclerosis or for wound healing.
  • substituted imidazo [1, 2-a] pyridine compounds of the general formula I below act as inhibitors on the nitrogen monoxide synthase and are particularly useful for the treatment of migraines, septic shock, neurodegenerative diseases, such as multiple sclerosis, Parkinson's disease , Alzheimer's disease or Huntington's disease, inflammation, inflammation pain, cerebral ischemia, diabetes, meningitis, arteriosclerosis or for wound healing.
  • the present invention therefore relates to the use of at least one substituted imidazo [1, 2-a] pyridine compound of the general formula I,
  • R ⁇ is an unsubstituted or at least monosubstituted ds-alkyl radical, an unsubstituted or at least monosubstituted C 2- 8 alkenyl radical, an unsubstituted or at least mono-substituted C 2-8 alkynyl radical, a C 3-8 cycloalkyl radical, a bonded via a C ⁇ -8 -A!
  • kylen group C 3-8 cycloalkyl radical an unsubstituted or at least monosubstituted aryl or heteroaryl radical, H, F, Cl, Br, I, CN, NO 2 , NH 2)
  • C ( O) R 5 , CO 2 H, CO 2 R 6 or OH, preferably for an unsubstituted or at least monosubstituted C ⁇ . 8- alkyl radical or H, particularly preferably H,
  • R 3 for an unsubstituted or at least monosubstituted
  • Ci-s-alkyl radical an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C2-8 alkynyl radical, a C 3-8 cycloalkyl radical, an over a C 3-8 cycloalkyl radical bonded with a Ci-s-alkylene group, an unsubstituted or at least monosubstituted aryl or heteroaryl radical, an unsubstituted or at least monosubstituted aryl radical bonded via a Ci-s-alkylene group or heteroaryl radical, CH 2 SR 8 , CH 2 OR 8 or H, preferably represents an unsubstituted or at least monosubstituted Ci-s-alkyl radical or H, particularly preferably H,
  • R 4 for H, for an unsubstituted or at least monosubstituted
  • Ci-s-alkyl radical an unsubstituted or at least monosubstituted C 2-8 alkenyl radical, an unsubstituted or at least monosubstituted C 2-8 alkynyl radical, a C 3-8 cycloalkyl radical, a C 3- heterocycly!
  • R 5 stands for a substituted for unsubstituted or at least mono-Ci-s-alkyl radical, an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C 2 - 8 alkynyl radical, a C 3-8 cycloalkyl radical, a bound via a Ci-s-alkylene group C 3-8 -cycloalkyl radical, a C.
  • R 6 for an unsubstituted or at least monosubstituted
  • Ci-s-alkyl radical an unsubstituted or at least mono-substituted C 2 -s alkenyl radical, an unsubstituted or at least monosubstituted C 2 _ 8 alkynyl radical, a C 3 .s cycloalkyl radical, an over a C - alkylene group bonded C 3 -s-cycloalkyl radical, an unsubstituted or at least monosubstituted aryl radical or for an unsubstituted or at least monosubstituted aryl radical bonded via a Ci-s-alkylene group, preferably represents an unsubstituted or at least monosubstituted Ci-s-alkyl radical or an unsubstituted or at least monosubstituted aryl radical,
  • R 7 for an unsubstituted or at least monosubstituted
  • Ci-s-alkyl radical an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C 2 - 8 alkynyl radical, a C 3-8 cycloalkyl radical, an over a C - alkylene group bonded C 3-8 cycloalkyl radical, an unsubstituted or at least monosubstituted aryl residue or an a Ci- ⁇ alkylene group bonded unsubstituted or at least mono-substituted aryl radical, preferably represents an unsubstituted or at least monosubstituted Ci-s-alkyl radical or an unsubstituted or at least monosubstituted aryl radical,
  • R 8 for an unsubstituted or at least monosubstituted
  • Ci-s-alkyl radical an unsubstituted or at least monosubstituted C 2 - 8 alkenyl radical, an unsubstituted or at least monosubstituted C 2 - 8 alkynyl radical, an unsubstituted or at least mono-substituted aryl radical, an over a Ci-s-alkylene group bound, unsubstituted or at least monosubstituted aryl or heteroaryl radical or for a C 3 . 8 -cycloalkyl radical, preferably for an unsubstituted or at least monosubstituted C ⁇ . 8 -alkyl radical or an unsubstituted or at least monosubstituted aryl or heteroaryl radical,
  • Ci-s-alkyl radicals are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso - pentyl, neo-pentyl, n-hexyl, 2-hexyl and n-octyl.
  • Preferred C 2 - 8 alkynyl radicals are selected from the group consisting of ethynyl, propynyl (-CH-C ⁇ CH, -C ⁇ C-CH3), butynyl, pentynyl, hexynyl and octynyl.
  • one or more hydrogen radical (s) is (are) preferably selected by a substituent from the group F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2) N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (heterocyclyl) 2 , N (alkyl-OH) 2 , NO, NO 2 , SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, NO, NO 2 , SH, S-alkyl, S-aryl, S-heteroary
  • the multiple substitution can take place with the same or with different substituents. If the substituent itself has an alkyl group, this is preferably selected from the group consisting of methyl, ethyl, CH 2 -OH and CF 3 .
  • C 3 .8 cycloalkyl group includes cyclic, for the purposes of the present invention, hydrocarbons having 3 to 8 carbon atoms which may be saturated or unsaturated, unsubstituted or at least mono-substituted, wherein the binding of the cycloalkyl radical to the basic framework of the general formula I can take place via any ring member of the cycloalkyl radical.
  • the C 3 .8 cycloalkyl residue selected from the group cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl is preferred.
  • C 3 is particularly preferred.
  • 8 - Cycloalkyl residue is a cyclohexyl residue.
  • C 3-7 heterocyclyl radical includes within the meaning of the present invention, a 3-, 4-, 5-, 6- or 7-membered cyclic organic radical which contains at least 1, optionally also 2, 3, 4 or has 5 heteroatoms in the ring system, where the heteroatoms may be the same or different and the cyclic radical may be saturated or unsaturated, but not aromatic and may be unsubstituted or at least monosubstituted.
  • the heterocyclyl radical can be bound to the basic structure of the general formula I via any ring member of the heterocyclyl radical.
  • the heterocyclyl residue can also be part of a bi- or polycyclic system.
  • Preferred heteroatoms are selected from the group consisting of nitrogen, oxygen and sulfur.
  • the C 3 is preferably.
  • -Heterocyclyl radical selected from the group Te rahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • aryl radical means aromatic hydrocarbons which can also be condensed with further saturated, at least partially unsaturated or aromatic ring systems, the bond between the aryl radical and the basic structure of the general formula I being via any ring member of the aryl residue can take place. If the aryl radical has more than one substituent, these can be the same or different and can be in any and possible position of the aryl radical.
  • the aryl radical is preferably selected from the group of unsubstituted or at least monosubstituted phenyl, anthracenyl, 1-naphthyl and 2-naphthyl.
  • the aryl radical is particularly preferably selected from the group of phenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 2,3-dihydroxyphenyl, 2,3-dimethoxyphenyl and 1-naphthyl.
  • heteroaryl radical stands for a 5-, 6- or 7-membered cyclic aromatic radical which has at least 1, optionally also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or can be different and the binding to the basic structure of the general formula I can take place via any and possible ring member of the heteroaryl radical. If the heteroaryl radical has more than one substituent, these heteroaryl substituents can be the same or different and can be present in any and possible position of the heteroaryl.
  • the heterocycle can also be saturated, at least partially unsaturated or aromatic Ring systems be condensed. Preferred heteroatoms are selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl radical is preferably selected from the group of unsubstituted or at least monosubstituted pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indolyl, indazolyl, purinyl, pyrimidinyl, indolizinyl, quinolinyl, isoquinol Quinazolinyl, carbazolyl, phenazinyl and phenothiazinyl.
  • heteroaryl radicals are selected from the group pyridin-2-yl, pyridin-3-yl, furan-2-yl, furan-3-yl, 5-hydroxymethylene-furan-2-yl, 5-nitro-furan 2- yl, 5- [1,3] dioxolane-furan-2-yl, 5-carboxylic acid furan-2-yl, thien-2-yl (2-thiophene), thien-3-yl (3-thiophene ) and 5-carboxylic acid-2-thiophene (5-carboxylic acid thien-2-yl).
  • the C 3 . 8- cycloalkyl, the C 3 . Heterocyclyl, the aryl or the heteroaryl radical is mono- or polysubstituted, we preferably include one or more, for example two, three or four times, substitution of one or more hydrogen atoms of the ring system with a substituent selected from the group F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-heterocyclyl, NH-alkyl-OH, N (alkyl ) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (heterocyclyl) 2 , N (alkyl-OH) 2 , NO, NO 2 , SH, S-alkyl, S-cycloalkyl, S- Aryl,
  • aryl residues are particularly preferred substituents selected from the group F, CF 3 , OH and O-CH 3 .
  • heteroaryl radicals particularly preferred substituents are selected from the group OH, O-CH 3 , CH 2 OH, NO 2 , CO 2 H, CO 2 ethyl and [1, 3] -dioxolane.
  • cycloalkyl radicals particularly preferred substituents are CO 2 H or CO 2 ethyl.
  • substituted imidazo [1, 2-a] pyridine compounds of the general formula I or their physiologically compatible salts used according to the invention have at least one center of asymmetry, they can be in the form of their racemates, their pure enantiomers, their pure diastereomers or in the form of a mixture from at least two of the aforementioned stereoisomers.
  • the substituted imidazo [1, 2-a] pyridine compounds of the general formula I can also be in the form of a mixture of their enantiomers or diastereomers. These mixtures can each have two or more of the respective stereoisomers in any mixing ratio.
  • Chiral substituted imidazo [1, 2-a] pyridine compounds of the general formula I are preferably used in enantiomerically pure form.
  • substituted imidazo [1, 2-a] pyridine compounds of the general formula I can be prepared by customary methods known to the person skilled in the art.
  • the compounds of the general formula I used according to the invention are preferably prepared by reacting a substituted 2-aminopyridine of the general formula II, in which R 1 and R 2 are as defined in the general formula I given above,
  • radicals R 3 and R 4 have the meaning according to the general formula I and X is halogen, preferably Cl, Br or I, with the elimination of water and hydrogen halide.
  • the process for preparing the compounds of the general formula I used according to the invention is advantageously carried out under conditions in which water and / or hydrogen halide are preferably removed continuously from the reaction mixture.
  • Hydrogen halide can preferably be bound by adding soluble or insoluble organic or inorganic bases and thus removed from the reaction mixture.
  • Water can preferably be removed from the reaction mixture by azeotropic distillation or by adding drying agents or hygroscopic substances.
  • substituted 2-aminopyridines of the general formula II and the ⁇ -halocarbonyl compounds of the general formula III are generally available on the market or can be prepared by customary methods known to those skilled in the art.
  • substituted imidazo [1, 2-a] pyridine compounds of the general formula I used according to the invention can be isolated both as a free base and as a salt by the process used for their preparation.
  • the free base of the particular compound of general formula I is usually after the reaction according to the invention described above Process and, if appropriate, subsequent workup are obtained by customary methods known to those skilled in the art.
  • the free base of the respective compound of general formula 1 obtained in this way or formed in-situ without isolation can then, for example by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, Formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid, are converted into the corresponding, physiologically acceptable salt.
  • an inorganic or organic acid preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid,
  • the conversion of the respective compound of general formula I into the corresponding hydrochloride can preferably also be carried out by adding a suitable organic solvent, e.g. Butan-2-one (methyl ethyl ketone), dissolved compound of general formula I can be obtained as a free base with trimethylsilyl chloride (TMSCI).
  • a suitable organic solvent e.g. Butan-2-one (methyl ethyl ketone)
  • dissolved compound of general formula I can be obtained as a free base with trimethylsilyl chloride (TMSCI).
  • substituted imidazo [1, 2-a] pyridine compound of the general formula I used in accordance with the invention is obtained in the form of its racemates or other mixtures of its various enantiomers and / or diastereomers by the preparation process according to the invention, these can be prepared by customary methods known to those skilled in the art Process separated and isolated if necessary. Examples include chromatographic separation processes, in particular liquid chromatography processes under normal pressure or under elevated pressure, preferably MPLC and HPLC processes, and processes of fractional crystallization.
  • Another object of the present invention is the use of at least one substituted imidazo [1, 2-a] pyridine compound of the general formula I given above as an inhibitor of nitrogen monoxide synthase for the manufacture of a medicament for the treatment of migraine, septic shock, neurodegenerative diseases, preferably Multiple sclerosis, Parkinson's disease, Alzheimer's or Huntington's disease, inflammation pain, cerebral ischemia, diabetes, meningitis, arteriosclerosis or for wound healing.
  • Another object of the present invention is the use of at least one substituted imidazo [1, 2-a] pyridine compound of the general formula I given above, with the proviso that the radicals R 3 and R 4 are not both for a 4-methoxyphenyl
  • the radicals R 1 and R 2 represent a C 4 alkyl radical, a C 4 alkoxy radical, an OH radical or a NO 2 radical, as an inhibitor of Nitric oxide synthase for the manufacture of a medicament for the treatment of inflammation.
  • the present invention also relates to the use of at least one substituted imidazo [1, 2-a] pyridine compound of the general formula I given above for the manufacture of a medicament for the treatment of migraines, septic shock, neurodegenerative diseases, preferably multiple sclerosis, Parkinson's disease, Alzheimer's or Huntington's disease, inflammation pain, cerebral ischaemia, diabetes, meningitis, arteriosclerosis or for wound healing.
  • Another object of the present invention is the use of at least one substituted imidazo [1, 2-a] pyridine compound of the general formula I given above, with the proviso that the radicals R 3 and R 4 are not both for a 4-methoxyphenyl
  • the radical is when the radicals R 1 and R 2 , the same or different, stand for a C 4 alkyl radical, a C 1 alkoxy radical, for an OH radical or for a NO 2 radical, for the preparation of a medicament to treat inflammation.
  • the corresponding pharmaceuticals can be in the form of liquid, semi-solid or solid pharmaceutical forms, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, Aerosols or in multiparticulate form, for example in the form of pellets or granules, are present and can also be administered as such.
  • the medicaments according to the invention usually contain further conventional, physiologically compatible pharmaceutical auxiliaries known to the person skilled in the art, which are preferably selected from the group consisting of carrier materials, fillers , Solvents, thinners, surfactants, colorants, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
  • auxiliaries known to the person skilled in the art, which are preferably selected from the group consisting of carrier materials, fillers , Solvents, thinners, surfactants, colorants, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
  • physiologically compatible excipients and the amounts to be used depends on whether the medicinal product is oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or local, for example on infections on the skin or mucous membranes and to be applied to the eyes.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
  • the amount of the particular compound of general formula I to be administered to the patient can vary and is dependent, for example, on the weight or age of the patient and on the type of application, the indication and the severity of the disease. Usually 0.1 to 5000 mg / kg, preferably 1 to 500 mg / kg, particularly preferably 2 to 250 mg, per kg of body weight of the patient are administered to at least one compound of the general formula I.
  • This assay allows the percentage inhibition of NO synthase to be determined by a compound of the general formula I used according to the invention by measuring the NOS activity when the compound acts. NO synthase is mixed together with radioactively labeled arginine and the respective compound of general formula I under suitable conditions. After stopping the NO formation reaction at a predetermined point in time, the amount of unreacted arginine is determined directly or indirectly. The comparison of this amount with the amount of arginine remaining in a mixture of NOS and arginine without addition of a compound of the general formula I and under otherwise identical conditions shows the percentage inhibition of NO- Synthase through the tested compound.
  • This assay can be carried out as follows:
  • the separation takes place via a filter plate membrane.
  • This NOS assay is particularly suitable for high throughput screening (HTS) on microtiter plates (MTP).
  • HTS high throughput screening
  • MTP microtiter plates
  • Radioactive arginine is used as the substrate in this HTS-NOS assay.
  • the assay volume can be selected between 25 ⁇ l and 250 ⁇ l depending on the type of microtiter plate (MTP).
  • MTP microtiter plate
  • cofactors and coenzymes are added.
  • the batches are incubated in this microtiter plate (assay MTP) according to step (a) at room temperature and, depending on the enzyme activity (units) used, is between 5 and 60 minutes.
  • the plate is placed in a cell harvester, which is equipped with an MTP that has a cation exchange membrane as a filter base (filter MTP).
  • NADPH tetrasodium salt
  • Order No. 1585363 R ⁇ CHE company
  • Enzyme preparation buffer 50 mM Tris-HCl with 1 mM EDTA: The pH of the
  • Buffer was set to 7.4 at 4 ° C.
  • Incubation buffer 50 mM HEPES with 1 mM EDTA; 1, 25 mM CaCl 2 and 1 mM dithiothreitol.
  • the pH of the buffer was adjusted to 7.4 at 25 ° C.
  • Rat cerebelli were used as the starting tissue. The animals were anesthetized and sacrificed, the brain tissue, the cerebellum, was dissected out, 1 ml of enzyme preparation buffer (4 ° C.) was added per rat cerebellum, and the mixture was digested with a Polytron homogenizer for 1 min at 6000 rpm. This was followed by centrifugation at 4 ° C for 15 min at 20,000 g and then decanting off the supernatant and portioned freezing at -80 ° C (discarding the precipitate). incubation:
  • the plate was then dried in a drying cabinet at 60 ° C. for 1 h. Then the bottom side of the filter MTP was sealed exactly from below with a "back seal”. Then 35 ⁇ l scintillator were pipetted in per well. Furthermore, the top of the plate was sealed with a "top seal”. After a waiting time of 1 hour, the plate was measured on the ß counter.

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Abstract

L'invention concerne l'utilisation de composés imidazo[1,2-a]-pyridine substitués et de leurs sels physiologiquement acceptables, comme inhibiteurs de monoxyde d'azote-synthase, et pour la production de médicaments.
PCT/EP2002/003795 2001-04-05 2002-04-05 Utilisation de composes imidazo[1,2-a]-pyridine substitues comme medicaments WO2002080914A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
MXPA03008965A MXPA03008965A (es) 2001-04-05 2002-04-05 Uso de compuestos de imidazo [1,2-a]-piridinas sustituidas como medicamentos.
CA002442996A CA2442996A1 (fr) 2001-04-05 2002-04-05 Utilisation de composes imidazo[1,2-a]-pyridine substitues comme medicaments
HU0401302A HUP0401302A2 (hu) 2001-04-05 2002-04-05 Helyettesített imidazo[1,2-a]piridin-vegyületek felhasználása gyógyszerként
JP2002578953A JP2004529141A (ja) 2001-04-05 2002-04-05 置換されたイミダゾ［１，２−ａ］ピリジン化合物を医薬として使用する方法
EP02727529A EP1372647A2 (fr) 2001-04-05 2002-04-05 Utilisation de composes imidazo 1,2-a]-pyridine substitues comme medicaments
US10/678,645 US20040142961A1 (en) 2001-04-05 2003-10-03 Utilization of substituted imidazo[1,2-a]-pyridine compounds in pharmaceutical formulations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10117183A DE10117183A1 (de) 2001-04-05 2001-04-05 Verwendung von substituierten Imidazo[1,2-a]-pyridinverbindungen als Arzneimittel
DE10117183.8 2001-04-05

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/678,645 Continuation US20040142961A1 (en) 2001-04-05 2003-10-03 Utilization of substituted imidazo[1,2-a]-pyridine compounds in pharmaceutical formulations

Publications (2)

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WO2002080914A2 true WO2002080914A2 (fr) 2002-10-17
WO2002080914A3 WO2002080914A3 (fr) 2003-01-03

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PCT/EP2002/003795 WO2002080914A2 (fr) 2001-04-05 2002-04-05 Utilisation de composes imidazo[1,2-a]-pyridine substitues comme medicaments

Country Status (9)

Country Link
US (1) US20040142961A1 (fr)
EP (1) EP1372647A2 (fr)
JP (1) JP2004529141A (fr)
CA (1) CA2442996A1 (fr)
DE (1) DE10117183A1 (fr)
HU (1) HUP0401302A2 (fr)
MX (1) MXPA03008965A (fr)
PL (1) PL366858A1 (fr)
WO (1) WO2002080914A2 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008078100A2 (fr) 2006-12-22 2008-07-03 Astex Therapeutics Limited Nouveaux composés
WO2009047522A1 (fr) 2007-10-12 2009-04-16 Astex Therapeutics Limited Composés hétérocycliques bicycliques utilisés comme inhibiteurs de la protéine tyrosine kinase
US8076354B2 (en) 2007-10-12 2011-12-13 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8481531B2 (en) 2009-04-15 2013-07-09 Astex Therapeutics Ltd Bicyclic heterocyclyl derivatives as FGFR kinase inhibitors for therapeutic use
US8722687B2 (en) 2009-04-15 2014-05-13 Astex Therapeutics Ltd Imidazo [1,2-A]pyridine derivatives as FGFR kinase inhibitors for use in therapy
US8796244B2 (en) 2008-06-13 2014-08-05 Astex Therapeutics Ltd Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
US8895745B2 (en) 2006-12-22 2014-11-25 Astex Therapeutics Limited Bicyclic heterocyclic compounds as FGFR inhibitors
EP3417912A1 (fr) 2005-12-23 2018-12-26 ARIAD Pharmaceuticals, Inc. Composants hétéroaromatiques bicycliques

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10247271A1 (de) * 2002-10-10 2004-08-26 Grünenthal GmbH Substituierte C-Imidazo[1,2-a]pyridin-3-yle
AU2007257311A1 (en) * 2006-06-02 2007-12-13 Cbb International Pty Ltd A monitoring system
EP2070927A4 (fr) 2006-09-13 2010-10-13 Kyowa Hakko Kirin Co Ltd Dérivé hétérocyclique fusionné
ES2393430T3 (es) * 2007-10-17 2012-12-21 Novartis Ag Derivados de imidazo[1,2-A]-piridina útiles como inhibidores de ALK
EP2348018A4 (fr) * 2008-09-25 2012-04-25 Kyorin Seiyaku Kk Dérivé biarylique hétérocyclique et inhibiteur de pde le renfermant en tant qu'ingrédient actif
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof
WO2014021383A1 (fr) 2012-07-31 2014-02-06 協和発酵キリン株式会社 Composé hétérocyclique à cycles condensés
WO2022188876A1 (fr) * 2021-03-11 2022-09-15 浙江大学 Composé hétérocyclique à cycle condensé et son utilisation, composition pharmaceutique le contenant et son utilisation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4382938A (en) * 1980-10-22 1983-05-10 Synthelabo Imidazo[1,2-a] pyridine derivatives and their application as pharmaceuticals
WO1996025414A1 (fr) * 1995-02-15 1996-08-22 Pharmacia & Upjohn Company Imidazo[1,2-a]pyridines pour le traitement du snc et de cardiopathologies
US5614531A (en) * 1994-02-19 1997-03-25 Merck Patent Gesellschaft Mit Beschrankter Haftung Adhesion receptor antagonists
US5891891A (en) * 1995-04-07 1999-04-06 Clarendon-Trading & Investimentos Lda Use of imidazo 1, 2-A! pyridine-3-acetamide derivatives for the therapeutic treatment of neuropsychiatric syndromes associated with disfunction of the neural circuits of the basal ganglia
US6013654A (en) * 1997-08-14 2000-01-11 Pharmacia & Upjohn Company Imidazo[1,2-A]pyridines for the treatment of CNS and cardiac diseases
WO2001027109A2 (fr) * 1999-10-08 2001-04-19 Grünenthal GmbH Derives de tert.-butyl-(methyl-imidazo[1,2-a]pyridine-3-yl)amine
DE10050663A1 (de) * 2000-10-13 2002-04-18 Gruenenthal Gmbh Verwendung von substituierten Imidazo[1,2-a]pyridin-, -pyrimidin- und pyrazin-3-yl-amin-Derivaten zur Herstellung von Medikamenten zur NOS-Inhibierung

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3269604D1 (en) * 1981-06-26 1986-04-10 Schering Corp Novel imidazo(1,2-a)pyridines and pyrazines, processes for their preparation and pharmaceutical compositions containing them
US4791117A (en) * 1986-09-22 1988-12-13 Ortho Pharmaceutical Corporation 2- or 3-aryl substituted imidazo[1,2-a]pyridines and their use as calcium channel blockers
EP0266890A1 (fr) * 1986-10-07 1988-05-11 Yamanouchi Pharmaceutical Co. Ltd. Dérivés d'imidazopyridine, leur production et compositions pharmaceutiques les contenant
AU6355190A (en) * 1989-06-13 1991-01-17 Smithkline Beecham Corporation Inhibition of interleukin-1 and tumor necrosis factor production by monocytes and/or macrophages
US5912248A (en) * 1995-11-16 1999-06-15 Eli Lilly And Company Excitatory amino acid receptor antagonists
DE19602855A1 (de) * 1996-01-26 1997-07-31 Byk Gulden Lomberg Chem Fab Neue 3-Methylimidazopyridine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4382938A (en) * 1980-10-22 1983-05-10 Synthelabo Imidazo[1,2-a] pyridine derivatives and their application as pharmaceuticals
US5614531A (en) * 1994-02-19 1997-03-25 Merck Patent Gesellschaft Mit Beschrankter Haftung Adhesion receptor antagonists
WO1996025414A1 (fr) * 1995-02-15 1996-08-22 Pharmacia & Upjohn Company Imidazo[1,2-a]pyridines pour le traitement du snc et de cardiopathologies
US5912246A (en) * 1995-02-15 1999-06-15 Pharmacia & Upjohn Company Imidazo 1,2-a!pyridines for the treatment of CNS and cardiac diseases
US5891891A (en) * 1995-04-07 1999-04-06 Clarendon-Trading & Investimentos Lda Use of imidazo 1, 2-A! pyridine-3-acetamide derivatives for the therapeutic treatment of neuropsychiatric syndromes associated with disfunction of the neural circuits of the basal ganglia
US6013654A (en) * 1997-08-14 2000-01-11 Pharmacia & Upjohn Company Imidazo[1,2-A]pyridines for the treatment of CNS and cardiac diseases
WO2001027109A2 (fr) * 1999-10-08 2001-04-19 Grünenthal GmbH Derives de tert.-butyl-(methyl-imidazo[1,2-a]pyridine-3-yl)amine
DE10050663A1 (de) * 2000-10-13 2002-04-18 Gruenenthal Gmbh Verwendung von substituierten Imidazo[1,2-a]pyridin-, -pyrimidin- und pyrazin-3-yl-amin-Derivaten zur Herstellung von Medikamenten zur NOS-Inhibierung

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3747441A1 (fr) 2005-12-23 2020-12-09 ARIAD Pharmaceuticals, Inc. Composants hétéroaryles bicycliques
EP3417912A1 (fr) 2005-12-23 2018-12-26 ARIAD Pharmaceuticals, Inc. Composants hétéroaromatiques bicycliques
US8513276B2 (en) 2006-12-22 2013-08-20 Astex Therapeutics Limited Imidazo[1,2-a]pyridine compounds for use in treating cancer
US8895745B2 (en) 2006-12-22 2014-11-25 Astex Therapeutics Limited Bicyclic heterocyclic compounds as FGFR inhibitors
WO2008078100A2 (fr) 2006-12-22 2008-07-03 Astex Therapeutics Limited Nouveaux composés
US8859583B2 (en) 2007-10-12 2014-10-14 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8859582B2 (en) 2007-10-12 2014-10-14 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8076354B2 (en) 2007-10-12 2011-12-13 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8071614B2 (en) 2007-10-12 2011-12-06 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
WO2009047522A1 (fr) 2007-10-12 2009-04-16 Astex Therapeutics Limited Composés hétérocycliques bicycliques utilisés comme inhibiteurs de la protéine tyrosine kinase
US8796244B2 (en) 2008-06-13 2014-08-05 Astex Therapeutics Ltd Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
US8722687B2 (en) 2009-04-15 2014-05-13 Astex Therapeutics Ltd Imidazo [1,2-A]pyridine derivatives as FGFR kinase inhibitors for use in therapy
US8481531B2 (en) 2009-04-15 2013-07-09 Astex Therapeutics Ltd Bicyclic heterocyclyl derivatives as FGFR kinase inhibitors for therapeutic use

Also Published As

Publication number Publication date
US20040142961A1 (en) 2004-07-22
JP2004529141A (ja) 2004-09-24
EP1372647A2 (fr) 2004-01-02
HUP0401302A2 (hu) 2004-12-28
WO2002080914A3 (fr) 2003-01-03
MXPA03008965A (es) 2004-02-12
PL366858A1 (en) 2005-02-07
CA2442996A1 (fr) 2002-10-17
DE10117183A1 (de) 2002-10-10

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